“Malaria remains a formidable global health challenge with approximately 608 000 deaths attributed to it in 2022, the majority occurring in sub-Saharan Africa,” says Dr Fortunate Mokoena, a senior lecturer in the North-West University’s (NWU’s) Faculty of Natural and Agricultural Sciences.
She adds that pregnant women and children under five years old are particularly vulnerable to its devastating effects. The region's tropical climate provides an ideal breeding ground for the Anopheles mosquito, the primary vector for Plasmodium, the parasite responsible for malaria transmission.
"While recent advancements include the development of vaccines, insecticides, and chemotherapeutic agents, these measures alone cannot fully eradicate the disease. Furthermore, the emergence of drug resistance underscores the urgent need for novel treatment strategies with distinct mechanisms of action.
“Thanks to efforts spanning 125 years, an effective malaria vaccine has been developed, and hopefully increased usage – especially in resource-limited settings – will help to curb transmission,” adds Dr Mokoena.
“In this endeavour, our project focuses on identifying potential new drugs for malaria treatment by targeting a crucial protein, PfHsp90 – which is vital for the malaria parasite's survival. Employing a combination of molecular dynamics simulations and biochemical assays, we aim to pinpoint and optimise promising drug compounds.”
“These compounds undergo severe testing on PfHsp90 in laboratory settings, evaluating their efficacy against both the malaria parasite and human cells. Through meticulous analysis of various assays, we ascertain the potential of these compounds as effective antimalarial agents,” she adds.
Dr Mokoena says their collaborative efforts have yielded promising results, with several compounds demonstrating potent activity against the asexual stage of the P. falciparum parasite, while selectively inhibiting PfHsp90 without adverse effects on human cells. Furthermore, in collaboration with medicinal chemists, they have identified additional scaffolds that can be optimised to enhance potency.
She explains that targeting PfHsp90 presents a promising strategy to mitigate drug resistance, as evidenced by the detrimental effects observed on parasite survival using known inhibitors. Leveraging computer-aided drug discovery techniques, they have identified compounds with significant antimalarial activity and minimal cytotoxicity to human cells, laying a solid foundation for further drug development.
“Our multidisciplinary team, based at the NWU’s Biochemistry subject group, comprises researchers with diverse expertise, including organic and computational chemistry, structural biology, and biophysical assays. Collaborations with institutions such as the University of Cape Town, Walter Sisulu University and the University of Venda, as well as support from organisations like Medicines for Malaria Ventures, have been instrumental in advancing our research objectives.”
She adds that the journey of drug discovery is not without its challenges, requiring patience, humility, and a collaborative spirit. “It is a testament to the collective effort of individuals from diverse backgrounds working towards a common goal: to alleviate the burden of malaria, particularly in Africa.”
Dr Mokoena, a grant recipient of the Grand Challenges Africa initiative at the Science for Africa Foundation, is spearheading targeted drug discovery efforts for malaria. Learn more about her groundbreaking work.
